03 01-06 approach to ataxia

Approach to Ataxia

ALOK SAHAY, MDAssistant Professor – Neurology

University of Cincinnati

3/1/06

Definition

literal meaning -without orderclumsiness loss of co-ordination

Genesis

cerebellum and its connecting pathways

proprioceptive sensory pathways

vestibular system

Cerebellar Dysfunction: Anatomy

Cerebellar parts Functions SignsPosterior

(Flocculo-nodular lobe)

Archicerebellum

Body equilibrium

Eye movements

Eye movement disorders: Nystagmus; Vestibulo-ocular reflex (VOR)Postural and gait dysfunction

Midline(Vermis; vermis of ant. lobe

pyramid , uvula and paraflocculus)

Paleocerebellum

Input from spinal cord

Muscle tone

Axial stance and gait

Truncal & gait ataxia

Hemisphere(middle portion of vermis,

cerebellar hemisphere)

Neocerebellum

Connected with Pons and cortex through thalalmus

Planning and initiation of movements

Regulation of fine limb movements

Limb ataxia:

Dysmetria, Dysdiadochokinesis,

"intention" tremor

Dysarthria

Hypotonia

Cardinal features - Cerebellar pathology

– Stance and gait– Poor regulation and coordination of skilled

movements (Dysmetria and dysdiadokinesia) – Eye movement disturbances– Altered Muscle tone (Hypotonia)– Speech (Dysarthria)

Core Symptoms

• Difficulty with balance of gait

• Clumsiness of hands

• Dysarthria

• Gaze problems

Manifestations- Stance and gait

– Wide based stance & Gait – Gait- staggering, irregular steps, lateral veering.– Cerebellar gait -visible or more prominent

– Sudden turn, Abrupt stops , Tandem walking

– Ataxic sensory gait • brisk leg movements• legs placed far apart to correct instability• steps of variable length• need for carefully watching the ground. • +ve Romberg's sign .

– Most of the autosomal recessive and dominant ataxias and with a known genetic defect are characterized by the coexistence of cerebellar and sensory ataxia

Limb coordination

• Asynergia- movements are broken into isolated subsequent steps , lack easiness/ smoothness

• Dysdiadochokinesia- impaired REM

• Dysmetria. there is an abnormal excursion in movements and errors in reaching a precise target

• Tests– finger-to nose, the finger-chase tests for the upper limbs– heel-to-knee and heel-to-tibia tests for the lower limbs.

• In coordination due to cerebellar disease is associated– with abnormal speed of the movements– to an excessive rebound phenomenon when an opposed motion is

suddenly released. ( due to a delay in contraction of the muscles, which normally would arrest the flexion of the limb)

– Speed of initiating the movement is also slow and there is irregularity in both acceleration and deceleration of movements

Tremor

• kinetic (intention) tremor

• static (postural) tremor may also occur.

• Related to hypotonia.

• In some cases of SCAs- myoclonus or chorea may be superimpose on postural tremor.

Muscle tone

• Hypotonia is a typical cerebellar sign.

• Wider excursion of hands on shaking the arms.

• Obliteration of the space between the volar aspect of the wrist and the deltoid.on a forced flexion of the arm at the elbow.

• In ataxic patient, the hypotonia is not a constant clinical sign.

– Present in FRDA1 patients, “pure” cerebellar syndromes- SCA6, 10, and 11 subtypes.

– In some other spinocerebellar disorders normal or increased muscle tone may also be found - SCA3 or MSA.

Speech- Dysarthria

• Altered articulation of words

• Abnormal fluency of speech.

• Scanning Dysarthria

• Slurring

Ocular Motor Functions

• Smooth pursuit movements• Saccades • Certain clinical cerebellar syndromes might have characteristic

patterns – FRDA1- fixation instability , square wave jerk, consistently

undershoot or overshoot the target during horizontal saccadic eye movements (saccadic dysmetria)

– ABL -progressive paresis of the medial rectus muscles with nystagmus of the adducting eye on lateral gaze was observed

– AR ataxias (some ) Oculomotor apraxia– AD ataxias-

• Fragmentation of smooth pursuit movements,• Saccadic dysmetria• Nystagmus • Saccadic slowing SCA1, SCA2, SCA3, SCA7, and SCA17• ophthalmoplegia -SCA2 SCA1 and SCA3

Classification

Congenital Hereditary Autosomal Dominant Autosomal Recessive Congenital DNA repair defects Metabolic disorders Mitochondrial Multisystem disorders X-linked Immune Miller-Fisher Multiple sclerosis Paraneoplastic Infections: CNS Acute ataxia: Viral Creutzfeldt-Jakob Meningitis

Mass lesion Abscess Neoplasm Sarcoid Paroxysmal Epilepsy Febrile Migraine Polyneuropathy Anti-MAG Syndrome GALOP Syndrome Sensory Neuropathy Large fiber Neuropathy Supratentorial Gait disorders Elderly Extrapyramidal Hydrocephalus

Systemic Amyloid Autoimmune Endocrine Hypoparathyroid Thyroid GI disorders Celiac disease; Sprue Vitamin E malabsorption Whipple's Toxins & Drugs Trauma Vascular Vestibular

Etiology

• Degenerative – MSA, Progressive myoclonic epilepsy• Stroke

– cerebellar, thalamic, brainstem, pontomedullary junction, lesions causing ataxic hemiparesis

• Tumors- Medulloblastoma, Astrocytoma, Ependymoma, Hemangioblastoma, Metastasis, Meningioma, CP angle schwanoma

• Toxic/ Metabolic- – Alcohol, – Hypoxia, – Hyperammonimias– Vitamin def. -B1, B12, Thiamine – Endocrine- hypothyroidism, hypoparathyroidism, hypoglycemia,– Thallium, bismuth, methyl mercury, methybromide, toulene– Drugs- PHT, CBZ, Brabiturates, Lithium, Cyclosporine, Methotrexate,

5FU, Serotinin syndrome

Etiology

• Paraneoplastic• Autoimmune

– Anti- GAD antibodies• Infectious/post-infectious-

– rubella– H.influenza– Varicella ( post infectious cerebellitis)– CJD

• Demyelinating- Multiple sclerosis• Other-

– Chiari malformation– Abscess– Hydrocephalus– Superficial hemosiderosis

• Ataxias of non cerebellar origin- Peripheral neuropathies

Paraneoplastic-cerebellardegenerations (PCD)

• associated with specific tumor type antineuronal (anti purkinje cell antibodies)

• late-onset ataxia and are characterized by a sub acute progressive course.

• Even if the cancer is found and successfuly the disorder may well not improve because cells are irreversibly damaged.

• Functional outcome best in anti-Ri, • Survival worse with anti-Yo and

anti- Hu, better with anti Tr and anti Ri

• Most common –– Gynecological & breast cancer– Lung cancer– Hodgkin's

• Small cell lung cancer– anti-Hu, anti-Ri ( ANNA-2),

anti-VGCC,anti-CRMP5/CV2* anti-amphiphysin

• ovarian cancer – anti-Yo ( PCA-1), anti-Ri,

anti-CRMP5/CV2• breast cancer

– anti-Yo, anti-Ri • Hodgkin’s disease

– anti-Tr and anti-mGluR1 • Testes-

– Anti Ma, Anti-Ta( Ma2)• Colon-

– Anti-HU

Antigliadin antibodies

• Celiac disease or sprue is interesting cause of ataxia• Celiac disease is gluten sensitive enteropathy• Cerebellar degeneration does not get better on gluten

free diet. • Up to 40% of sporadic ataxias have anti-gliadin

antibodies• Similar % in genetic ataxias• Importance is not known.

• Bushara KO,Goebel SU, Shill H,GoldfarbLG,Hallett M (2001) Gluten sensitivityin sporadic and hereditary cerebellarataxia.Ann Neurol 49:540–543

Genetic Ataxias

• Mendelian AR and AD ataxias have a higher frequency than other genetic ataxias. • Prevalence – 1/50,000 - Friedreich’s ataxia (FRDA1)

• 1/100,000 - Ataxia Telangectasia (AT), dominant SCAs • AR ataxias

– Multi-system disorders with extra-neural signs and symptoms - FRDA1 and AT – Main mechanisms - loss of protein function,

• the control of energy output and oxidative stress -FRDA1, AVED, ABL, possibly Cayman ataxia;

• the control of DNA maintenance and the cell cycle -AT, AOA1 and AOA2, SCAN• AD ataxias - restricted to the central nervous system.

– Mutant protein with a longer-than-normal poly glutamine stretch. – Toxic gain-of-function of the aberrant protein – Longer expansions-earlier onset, more severe disease in subsequent generations– Diagnostic pathological feature-OPCA-(most common presentation of SCA+)

• AD episodic ataxias (EA)– Point mutations in the potassium channel gene, KCNA1,- EA 1– Point mutations in the CACNL1A4 gene - EA2

Hereditary Ataxias: Dominant

Spinocerebellar Ataxias Adult-onset leukodystrophy Branchial myoclonus &

Spastic paraparesis CAPOS syndrome Deafness & Narcolepsy DRPLA: DRPLA protein;

CAG repeat;12p13 Episodic ataxia

with Myokymia (EA1): KCNA 1; 12p13

Paroxysmal (EA2): a1A Ca++ channel; 19p13

with Choreoathetosis & Spasticity: 1p

Holmes ataxia Mental retardation: 19q13 Multiple hamartoma syndrome:

PTEN; 10q23 Myelocerebellar Nystagmus Parenchymal degeneration Prion disease: Prion protein; 20p12 Spastic ataxia syndromes Thermoanalgesia & loss of

fungiform papillae Tremor, Essential: 3q13 Vermal aplasia Von Hippel-Lindau Syndrome:

VHL protein; 3p26

Hereditary Ataxia: Recessive

Ataxia Telangectasia: ATM; 11q22

Ataxia telangectasia-like: MRE11; 11q21

Baltic Myoclonus (Unverricht-Lundborg): Cystatin B; 21q22

Cayman ataxia: 19p13 Cerebelloparenchymal

disorders (CPD): II, III, IV, V Charlevoix-Saguenay -

Spastic Ataxia: Sacsin; 13q12

Cockayne Syndrome (5) Cytochrome c Oxidase I Early onset with retained

reflexes (EOCA): 13q12 Friedreich ataxia: 9q13

Infantile Onset Spinocerebellar Ataxia: 10q23

Leukoencephalopathy with vanishing white matter: 3q27

Marinesco-Sjögren Posterior column + Retinitis

pigmentosa: 1q31 Salla syndrome: SLC17A5; 6q14 Vitamin E deficiency: a-

tocopherol transfer protein; 8q13 Xeroderma pigmentosum Other Congenital ataxias• DNA repair defects• Metabolic,Mitochondrial• Multisystem disorders

Hereditary Ataxia: Metabolic,Congenital &X-linked

METABOLIC Abetalipoproteinemia Biotinidase Deficiency Cerebrotendinous Xanthomatosis Gamma-Glutamyl Cysteine Synthetase Hartnup Hyperammonemic Hypobetalipoproteinemia L-2 Hydroxyglutaric academia Maple Syrup Urine Disease Niemann-Pick, Type C Recessive ataxias Refsum Disease Wilson's Disease

CONGENITAL Aprosencephaly & cerebellar dysgenesis Ataxia-Deafness: X Ataxia-Mental retardation: Xq24-q27 Behr syndrome Carbo.deficient glycopr Cerebellar ataxia 1 (CLA1) Cerebellotrigeminaldermal dysplasia COACH Congenital muscular atrophy Dandy-Walker Fibroblast GF-3 Gillespie Hoyeraal-Hreidarsson Syndrome: Dyskerin; Xq28 Joubert: 9q34 Lissencephaly X-linked congenital ataxia 1,2

X-LINKED Arts Syndrome CLA2 Pyruvate dehydrogenase E1-a Sideroblastic anemia

Spinocerebellar Ataxia (SCA)

Dominant SCA syndromes have many overlapping signs: Difficult to distinguish on clinical grounds

Common features to all: Gait ataxia; Dysarthria

Features in some ataxias: Ocular D; Extrapyramidal; Peripheral nerve; Intellectual D; Seizures

Features with some predictive value for specific gene defects

Epidemiology

ADCA- 5/100,000 FA 5/100,000 Among ADCAs

SCA 1 - 5.6 % SCA 2 - 15.2 % SCA 3 - 20.8 % SCA 6 - 15.2 % SCA 7 - 4.5 %

-ve F/H - 6.8% + CAG repeats, 5.2% FA* apparently recessive- 4.4% +CAG rpts, 11.24% FA

Moseley et al: Neurology 1998; 54,:1408-1421

Relationship between ADCAs and SCAs

ADCA type SCA type

I -Cerebellar plus(Pyramidal, Extra-pyramidal,

Ophthalmoplegia, & Dementia) 1,2,3,4,12,16,17, DRPLA

II Cerebellar + pigmentary maculopathy 7

III pure cerebellar ± Mild

pyramidal signs 5,6,8,11,14,15,22

Ataxia and epilepsy 10

Early onset with mental retardation 13

SCA: Clinical Syndromes

•SCA 1: Hypermetric saccades; ++Tendon reflexes; Evoked motor potentials Long conduction times •SCA 2 Slowing saccads; Myoclonus or action tremor •SCA 3/Machado-Joseph: Gaze-evoked nystagmus; Prominent spasticity or neuropathy •SCA 4: Cerebellar syndrome; Sensory neuropathy •SCA 5: Pure cerebellar syndrome •SCA 6: Pure cerebellar syndrome; -ve family history; Late onset > 50 •SCA 7: Retinal degeneration; Hearing loss; Onset in 1st decade •SCA 8: Pure cerebellar syndrome •SCA 10: Pure cerebellar syndrome ± Seizures •SCA 11: Pure cerebellar syndrome •SCA 12: Early arm tremor; Late dementia •SCA 13: Early childhood onset; Mental retardation •SCA 14: Ataxia; Myoclonus (with early onset)

Polyneuropathy in SCA

Axonal; Sensory or Sensory-Motor

SCA1: 42%; More with CAG repeats

SCA2: 80%

SCA3: 54%; More with fewer CAG repeats

SCA4: Sensory loss

SCA7: 0%

SPINOCEREBELLAR ATAXIA 1 ;SCA 1SPINOCEREBELLAR ATORHY I

OLIVOPONTOCREBELLAR ATORPHY I; OPCA 1OPCA I

MENZEL TYPE OPCA

CLINICAL SYNOPSIS Neurological:

Miscellaneous:

Labs:

Gene Map Locus:6p 22-p23 CAG 40-83 ( N 6-40) cerebellar ataxia chorea upper motor neuron signs extensor planter, hyperreflexia lower bulbar palsies gaze paresis 50% , slow saccades 100 % scanning and explosive speech inco-ordination

onset third/fourth decade earlier onset when inherited from father , anticipation

axonal neuropathy atrophy of cerebellum, pons, olive,lower CN nuclei,

dorsal columns and spinocerebellar tracts Reduced aspartic acid in brain mutant protein Ataxin- 1, Intranuclear inclusions

SPINOCEREBELLAR ATAXIA 2; SCA 2SPINOCEREBELLAR ATROPHY II

OLIVOPONTOCEREBELLAR ATROPHY, HOLGUIN TYPEOLIVOPONTOCEREBELLAR ATROPHY 2

SPINOCEREBELLAR ATAXIA, CUBAN TYPE

CLINICAL SYNOPSIS

Neurological

Limbs Miscellaneous

Labs

Gene Map Locus :12q23-24.1 CAG 34-59 ( N 14-31)

adult onset progressive cerebellar ataxia palatal myoclonus , myokimia slow saccadic eye movements 100% dysarthria ophthalmoparesis 40%, optic atrophy pyramidal signs 20% peripheral sensory loss, abolished tendon reflexes dementia extrapyramidal signs in Tunisian kindred bladder dysfunction no parkinsonian features

flexion contracture of legs onset 2 - 65 yrs, 40% < 25 yrs, anticipation, may be

sporadic

involvement of cerebellum & inferior. olivary nuc.,pons,spinal cord Ataxin - 2 , nuclear aggregates

SPINOCEREBELLAR ATAXIA 3 ; SCA 3MACHODO-JOSEPH DIEASE,MJD

AZOREAN NEUROLOGIC DISEASENIGROSPINODENTATAL DEGENERATION, SPINOPONTINE AROPHY

CLINICAL SYNOPSIS Neurological:

Eyes Muscle Endocrinal Miscellaneous

Labs

Gene Map Locus : 14q32..1 CAG 56-86 (N -12-38) ataxia parkinsonian features facial and lingual fasciculations muscle fasciculations loss of leg reflexes cerebellar tremors extensor planter

bulging eyes, limited eye movements, nystagmus muscle atrophy diabetes mellitus onset after 40 yr, paternal> maternal anticipation I- earlier onset(5-30), II- intermediate(~36 yr), III- cerebellar,PN,Optho(>40yr), IV- parkinsonian,

fasciculations, sensory(38-47yr levodopa responsive)

neuronal loss and gliosis in SN, STN,GP,Dedtate nuclei, nuclei pontis, vestibular & cranial nerve nuclei,,post.columns and ant. Horns

abnormal EOG ATAXIN- 3, nuclear/cytoplasmic inclusions

SPINOCEREBELLAR ATAXIA 4; SCA 4SPINOCEREBELLAR ATAXIA WITH SENSORY AXONAL NEUROPATHY

CLINICAL SYNOPSIS

Neurological

Miscellaneous

Labs

Gene Map Locus :16q22.1

late onset spinocerebellar ataxia dysarthria 50% diminished vibration and joint position sense absent ankle jerk reflexes, 100% absent knee jerks , 85% areflexia , 25% extensor planter 20% no opthalmoplegia onset fourth or fifth decade anticipation ?

MRI cerebellar atrophy axonal sensory neuropathy

SPINOCEREBELLAR ATAXIA 5; SCA5

CLINICAL SYNOPSIS

Neurological

Miscellaneous

Gene Map locus ; 11p12-q12

spinocerebellar ataxia dysarthria

onset 10 -68 yrs ?descendents from paternal

grandparents of President Abraham Lincoln

one family from NE France anticipation probable slow course

SPINOCEREBELLAR ATAXIA 6; SCA6

CLINICAL SYNOPSIS

Neurological

Miscellaneous

Labs

Gene Map Locus: 19p13.1-p13.2 CAG 21-31 ( N 4-20 )

spinocerebellar ataxia frontal lobe signs, dysarthria dementia mild ophthalmoplegia, down beat & gaze evoked- nystagmus peripheral neuropathy sense of imbalance on turning seizures

other conditions associated with 19p13 are : hemiplegic migraine, familial periodic cerebellar ataxia

onset ~30 if 25-27 repeats, ~40-50 if 21-24 repeats sporadic 27%

cerebellar atrophy -1A voltage dependent calcium channel ( CACNL1A) no inclusion bodies

SPINOCEREBELLAR ATAXIA 7: SCA7OLIVOPONTOCEREBELLAR ATROPHY -III,OPCA 3

OPCA WITH RETINAL DEGENERATIONOPCA WITH MACULAR DEGENERATION & EXTERNAL OPHTHALMOPLEGIA

ADCA, TYPE 2

CLINICAL SYNOPSIS Neurological

Eyes

Miscellaneous Labs

Gene Map Locus -3p21.1-p12 CAG 38->200 (N 17) cerebellar ataxia chorea periodic slight head tremor pyramidal signs, dysarthria brisk deep tendon reflexes hearing loss variable retinopathy 43% visual loss ( VA 83%, blindness 28%), tritan (blue

yellow) color blindness ophthalmoplegia(70%) macular degeneration, optic atrophy( 69%) circumpapillary degeneration slow saccades anticipation , paternal transmission larger repeats degeneration of cerebellum, basis pontis, inferior

olive, & retinal ganglion cells , Ataxin-7, intranuclear inclusions

SPINOCEREBELLAR ATAXIA 8: SCA 8

CLINICAL SYNOPSIS

Neurological

Miscellaneous

Labs

Gene map locus- 13q21 CTG 100-155 ( N 15-91)

cerebellar signs impaired smooth pursuit(100%) horizontal nystagmus (67%) dysarthria ( 100%) ataxia

Progression slow , maternal anticipation more prominent

onset 40-50 yrs

MRI cerebellar vermis& hemisphere atrophy



Miscellaneous

Gene Map locus- 12q13 predominantly cerebellar

dysfunction gait and limb ataia dysarthria nystagmus occassional seizures

Mexican family anticipation marked

especially with paternal inheritance

? Calcium channel


CLINICAL SYNOPSIS

Neurological

Miscellaneous

Labs

Gene map locus - 15q14-21.3

cerebellar ataxia 100% horizontal > vertical nystagmus

(100%) dysarthria (100%) Limb ataxia (93%) Hyper reflexia(100%) no extrapyramidal ,weakness or

sensory signs

normal life expentancy

normal nerve conduction isolated cerebellar atrophy


CLINICAL SYNOPSIS

Neurological

Miscellaneous

Labs

Gene map locus 5q31-q33 CAG 66-93 ( N-<29 )

Tremor arm & head gait & limb ataxia hyperreflexia paucity of movements eye movement abnormalities dementia in oldest patients

onset 8-55 yr German family

MRI cortical and cerebellar atrophy protein phosphatease 2, R2B , brain

specific regulatory subunit of PP2A involved in regulatory processes


CLINICAL SYNOPSIS

Neurological

Miscellaneous

Labs

Gene map locus 19q13.3-q13.4 Ataxia legs > Arms dysarthria nystagmus motor dysfunction poor running inability to walk by 4-6th

decade hyperreflexia mental retardation

French family 7/8 females onset early childhood no anticipation MRI pontocerebellar atrophy


CLINICAL SYNOPSIS

Neurological

Miscellaneous

Labs

Gene map locus-19q13.4-qter

Ataxia legs >arms axial myoclonus( younger in

onset<27 yr) tremor in exteremities and

head ( younger onset) hyperreflexia

Japanese family ? Anticipation

MRI Cerebellar atrophy

DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; DRPLAMYOCLONIC EPILEPSY WITH CHOREOATHETOSIS

NAITO-OYANAGI DISEASE; NODATROPHIN 1, INCLUDED

CLINICAL SYNOPSIS

Neurological:

Miscellaneous:

Labs:

Gene Map Locus: 12p13.31 CAG 49-75 (N<24)

Myoclonus epilepsy ( longer repeats) Dementia Ataxia Choreoathetosis

Onset usually in the 20s and death in the 40s

commaon in Japan

Combined degeneration of dentatorubral and pallidoluysian systems

DRPLA protein , neuronal cytoplasm

EPISODIC ATAXIA, TYPE 1; EA1PAROXYSMAL ATAXIA WITH NEUROMYOTONIA, HEREDITARY

EPISODIC ATAXIA WITH MYOKYMIA; EAMATAXIA, EPISODIC, WITH MYOKYMIA; AEM; AEMK

MYOKYMIA WITH PERIODIC ATAXIA


Miscellaneous

Labs

Treatment

Gene Map Locus: 12p13 Myokymia Continuous muscle movement Periodic ataxia Continuous muscle movement Periodic ataxia

Ataxic attacks provoked by abrupt postural change, emotional stimulus, and caloric-vestibular stimulation, startle

Onset in second decade Hand posture resembling carpopedal spasm

Potassium voltage-gated channel gene mutation Continuous spontaneous activity on EMG at rest Muscle biopsy consistent with denervation, with

enlargement of muscle fiber Phenytoin, not Acetazolamide

EPISODIC ATAXIA, TYPE 2; EA2PERIODIC VESTIBULOCEREBELLAR CEREBELLOPATHY,

HEREDITARY PAROXYSMAL ATAXIA, FAMILIAL PAROXYSMAL ATAXIA

ACETAZOLAMIDE-RESPONSIVE PAROXYSMAL CEREBELLARATAXIA; APCAEPISODIC ATAXIA, NYSTAGMUS-ASSOCIATED CEREBELLAR ATAXIA


Miscellaneous

Labs

Treatment

Gene Map Locus: 19p13 Episodic ataxia Cerebellar ataxia Vertigo Diplopia Downbeat nystagmus

Ataxia precipitated by stress or excitement, not by startle

attacks last 1/2 to 6 hrs.

point mutation alpha 1A calcium voltage dependant channel

allelic with SCA6 & familial hemiplegic migraine

Response to oral acetazolamide

CHOREOATHETOSIS/SPASTICITY, EPISODIC; CSECHOREOATHETOSIS, PAROXYSMAL, WITH EPISODIC ATAXIA

CHOREOATHETOSIS, KINESIGENIC, WITH EPISODIC ATAXIA AND SPASTICITYDYSTONIA 9; DYT9


Miscellaneous

Treatment

Gene Map Locus: 1pNeuro : Paroxysmal choreoathetosis. Episodic ataxia. Spasticity. Increased tendon reflexes. Pyramidal signs in legs. Involuntary movements. Dystonic limb posture. Imbalance. Dysarthria. Perioral and leg paresthesias.

Headache. Double vision. Onset from 2 to 15 years. Physical exercise, emotional

stress, lack of sleep, and alcohol precipitate symptoms.

acetazolamide

Episodic AtaxiasName Chromos

omeMutation Protein Clinical

EA type 1 12p Missense K-channel, KCNA1

Interictal myokimia eyes, lips and fingers

PHT, Diamox

EA type 2 l9p Missense α-component the VDCA CACNL1A4

Attacks of ataxia, dysarthria, N, V, Diplopia, osciloscopia minutes to day. Interictal nystagmus or mild ataxia. Provoked by exercise and stress not startle. ½ pts have headache. Diamox, 4 aminopyridinesame gene as SCA -6 but nature of mutation differs

EA type3 Episodic vestibulo-cerebellar ataxia, Defective smooth pursuit, gaze evoked nystagmus, vertigo

EA type4 Vestibular ataxia, vertigo, tinnitis, interictal myokymia - Diamox

EA with

Paroxysmal choreoathetosis & Spasticity

1p Onset 2-15 yr

Attacks of ataxia, involuntary movements , dystonia or extremities , parasthethiasa and headache 20 minutes 2/day-2/yr alc, fatigue, stress, exercise- Diamox

EA type 5 2q CACNβ4 One family

FRIEDREICH’S ATAXIA

CLINICAL SYNOPSIS Gene Map Locus: 9q13 GAA 66->1700 ( N< 42)

Neurological: Cerebellar ataxia Dysarthria Nystagmus Incoordined limb movements Diminished or absent tendon reflexes Babinski sign Impaired position & vibratory sense

Hypoactive knee and ankle jerks Cardiac : Hypertrophic cardiomyopathy ,CHF, Muscular subaortic stenosis Skel : Pes cavus , Scoliosis, Hammer toe Metabolic : Diabetes mellitus

Lab : Abnormal intranscription of protien FRATAXIN (resposible for Iron efflux from mitochondria)

Abnormal- motor and sensory nerve conduction, EKG, ECHO,MRI

Evaluation

• History & Physical Examination• Careful family history• Standard laboratory including lipids and thyroid• MRI Brain• Autonomic testing ( Sphincter EMG)• Genetic testing• Toxic screen, Vitamin E • Antibodies- paraneoplastic, antigliadin

Clinical History

• Accurate family history• Look for anticipation- earlier onset , heavier clinical

expression in subsequent generations ( SCA 2,7)- gene mutated parent is still asymptomatic or died before developing clinical symptoms.

• Consanguity - recessive • Age of onset – earlier in AR( exceptions-late onset

FRDA1, infantile cases of SCAs e.g. SCA2, SCA7)• Origin of families-

– SCA3 - Portugal, Brazil, India, rare in Italy SA– AVED – Southern Mediterranean– AOA1 – Portugal, Japan– Cayman Ataxia- Grand Cayman Island

Ataxia Rating Scales

• International Co-operative Ataxia Rating scale (ICARS)

– Evaluation of efficacy of ataxia treatments– Semi-quantitative 100 point scale – 19 items divided in 4 sub-scores

• Posture and gait• Kinetic functions• Speech• Ocular movements

• Trouillas et al. J International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology J Neurol Sci. 1997 Feb 12;145(2):205-11

DIAGNOSIS Recognize progressive ataxia syndrome and associated features

Oculomotor : slow saccades

Bulbar : facial, temporal, tongue atrophy, fasciculation, cough, dysphagia

UMN : brisk reflexes, spasticity, Babinski

Extrapyramidal : bradykinesia, plastic rigidity, dystonias, chorea

Cortical : late cognitive decline, myoclonus, seizures

Visual : macular, retinal lesion, optic atrophy

Peripheral Nervous System : sensory loss, hypo/areflexia, muscle atrophy,weakness

DIAGNOSIS Continued

Recognize typical family history Exclude non inherited causes of ataxia

Establish specific biochemical error

Establish specific gene mutation

• MS, strokes , tumors, alcohol, B12, ANA, hypothyroid, basal meniningitis, paraneoplastic Anti-Yo, -Ri, - Hu, Anti-gliadin antibodies, Toxic screen, Vit E levels

• hyperammonemias, hexose aminodase def Wilson's, abetalipoprotienemia, aminoacidurias,

• SCA1,2,3,6,7,8,DRPLA,FA,EA

Clues to SCAsAge at onset: childhood onsetSCA 7, 13, DRPLA Young adult: SCAl, 2, 3, 21older

adult: SCA 6

Prominent anticipation SCA 7, DRPLA

Upper motor neuron signs SCA 1,3, 7,12Some in SCA 6, 8RareinSCA2

Slow saccades Early, prominent: SCA 2,7, 12 Late: SCA 1,3 Rare: SCA6

Extra pyramidal signs Early chorea:DRPLA, Akinetic-rigid, Parkinson: SCA 2, 3,21

Generalized reflexes SCA 2,4, 19 ,21 Late: SCA 3Rare: SCA 1

Visual loss SCA7

Dementia Prominent: SCA 17, DRPLA Early: SCA 2,7 Otherwise: rare

Myoclonus SCA 2, 14

Tremor SCA 12*, 16, 19

Seizures SCA 10

INVESTIGATIONS: Reasonable Approach

CBC, electrolytes, glucose, BUN, creatinine

ANA Thyroid function tests Fasting Total Cholesterol Alpha-FP Immunoglobulins (IgE,

IgA) Drug screen Vitamins B12 and E Anti -Yo, -Ri, -Hu, -gliadin

antibodies

MRI Electrodiagnostic

• Nerve conduction velocities

• ECG • ECHO• Sphincter EMG

Modified from Hallett 2000

Laboratory

• Few recessive forms with biochemical abnormalities• ↓ Vitamin A – AVED• ↓ Vit. E, A, Lipoprotein in ABL ( acanthocytes with

absence apo-B lipoproteins• AT- ↑ AFP, ↓immunoglobulins• AOA1- ↑Chol, ↓ Alb• AOA2 - ↓ AFP• Late onset ataxia- paraneoplastic antibodies,

antigliadin antibodies

Imaging

CT

MRI

PET

Cerebellum, brainstem atrophy, enlarged IV ventricle

Above + T2 signal putamen, substantia nigra, inferior olive, pontine & dentate nuclei

Detects subclinical nigrostriatal dysfunction in OPCA Glucose utilization in cerebellar hemisphere,

frontal, prefrontal area,brainstem

Neuro-radiology

• FRDA- cervical spinal cord atrophy, mild cerebellar atrophy• Predominant vermian atrophy – AR ataxia- AT, AOA1,

AOA2, Cayman Ataxia, SCAN• Congenital ataxia – cerebellar hypoplasia or vermian aplasia• Joubert syndrome – absence of cerebellar vermis and “molar

tooth sign” at cerebellar & mid brain junction• Fragile X associated tremor/ataxia syndrome (FXTAS)-

– mild to moderate cerebral & cerebellar atrophy– Increases T2 signal in deep white matter of cerebellar hemisphere &

middle cerebellar peduncles• Cerebellar Atrophy- most common finding

– Pure cerebellar – SCA 6,10,11– Variable atrophy- cortex , brains tem , striatum, spinal cord – Ataxia

plus

MANAGEMENT

Genetic counseling -- inheritance pattern, risk to relatives, predictive value, prenatal test , implication for insurability, employment, relationships, psychological impact

OT/PT

Vision

Speech therapy

Bladder management

Pharmacological Therapy

PHARMACOLOGICAL THERAPY

Serotinin System

Cholinergic System

GABA

Dopamine

Neuropeptide

Glutamine

L 5HT Trouillas 1993 Lisuride Infusion Heinz et al 1992 improve d

performance 3/4 Buspirone Lou et al 1995 improved

9/20

Physostigmine , choline , lecithin

Isonex, Pyridoxine , Primidone

Clozapine Parson 1993 improved psychiatric symptoms

Levodopa TRH, DN-1417

Amantadine Botez1991,96 ~35 % improvement in UE Ataxia in 30 pts SCA 1,2,3,5

References

1. Nature Genetics 1996;14:237-2382. SCA1: Hum.Mol.Genet. 1995;4(9):1585-903. SCA2: Hum.Mol.Genet.1997;6(5):709-7154. SCA3: Ann.Neurol. 1996;39(4):490-99; J.Neurol.Sci. 1995;132(1):71-

75 5. SCA4: Am.J.Hum.Genet. 1996;59(2):392-99 6. SCA5: Nat.Genet. 1994;8(3):280-847. SCA6: Nat.Genet. 1997;15:62-69; Hum.Mol.Genet. 1997;6(8):1289-

93; Hum.Mol.Genet. 1997;6(8):1283-878. SCA7: Am.J.Hum.Genet. 1996;59:1328-36; Nat.Genet. 1997;17:65-709. SCA8: Nature Genetics 1999;21:379-38410. SCA10: Am J Hum Genet 1999;64:594-59911. SCA11: Am J Hum Genet 1999;65:420-42612. SCA12: Nature Genet 1999;23: 391-39213. SCA13: Am J Hum Genet 2000;67 (July)14. SCA14: Ann Neurol 2000;48:156-163

Resources

National Ataxia Foundation 2600 Fernbrook Lane, Suite 119 Minneapolis, MN 55447 Phone: 763-553-0020 Fax: 763-553-0167 E-mail: [email protected] Web: www.ataxia.org

Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing

Web: depts.washington.edu/neurogen/AtaxiaBrochure99.pdf

WE MOVE (Worldwide Education and Awareness for Movement Disorders) 204 E 84th St New York, NY 10024 Phone: 212-875-8312; 1-800-437-MOV2 , Fax: 212-875-8389 Email: [email protected] Web: www.wemove.org

International Network of Ataxia Friends (INTERNAF) Web: http://internaf.merseyside.org

Table 1. Autosomal Dominant Cerebellar Ataxias: Molecular Genetics

Disease Name

Locus Gene ProteinNormal CAG#

Abnormal 1 CAG#

Test Availability

SCA1 6p23 SCA1 Ataxin 1 6-40 40-83Clinical

SCA2 12q24.1 SCA2 Ataxin 2 14-31 34-400 Clinical

SCA3 14q21 SCA3 SCA3/ MJD1 12-38 55-86 Clinical

SCA4 16q22.1 SCA4 --- --- --- Research

SCA5 11 SCA5 --- --- ---

SCA6 19p13.1- p13.2 CACNAIA

Alpha 1A voltage dependent calcium

channel 4-20 21-31

SCA7 3p21.1- p12 SCA7 Ataxin 7 7-17 38->200 Clinical

SCA8 13q21 SCA8 --- (CTG) 15-91

(CTG) 100-155

Clinical

SCA9 Category not

assigned

SCA10 22q13 SCA10

--- --- ---

Research SCA11 15q14 -q21

SCA12 5q31SCA12

Protein phosphatase 2A <29 66-93

SCA13 19q13SCA13

--- --- --- Research

DRPLA 12p CTG-B37

Atrophin 1 3-36 49-88 Clinical

EA1 12p13 KCNA-

1KV1.1 --- ---

Research

EA2 19p13.1- 13.2 CACNAIA

Alpha 1A voltage dependent calcium channel

--- ---

1

Table 2. Autosomal Dominant Cerebellar Ataxias: Clinical Features

Diseas

e Name

Frequency in ADCA

Average Onset (Range in

Years)

Average Duration (Range in

Years)

Distinguishing Features (All have gait ataxia)

SCA16%

(5-27) 4th decade

(<10 to >60) 15

(10-28) Pyramidal signs,

peripheral neuropathy

SCA215%

(13-24)

3rd - 4th decade

(<10 to >60)

10 (1-30)

Slow saccadic eye movement, peripheral neuropathy, decreased DTR's, dementia

SCA321%

(11-36) 4th decade (10-

70) 10

(1-20)

Pyramidal and extrapyramidal signs; lid retraction, nystagmus, decreased saccade velocity; amyotrophy

fasciculations, sensory loss SCA4

Rare 4th - 5th decade

(19-59) Decades Sensory axonal

neuropathy

SCA5

Rare 3rd - 4th decade (10-68)

>25 Early onset, slow course

SCA6 15% 5th - 6th decade (19-71) >25 Sometimes episodic ataxia, very slow progression

SCA7 5% 3rd - 4th decade

(1/2 - 60)

20 (1-45; early onset

correlates with short duration)

Visual loss with retinopathy

SCA8 2-5% 39 (18-65) Normal lifespan Brisk DTRs and decreased vibration sense

SCA9

Category not

assigned

SCA10 Rare 36 9 Occasional seizures

SCA11 Rare 30 (15-70) Normal lifespan Mild, remain ambulatory

SCA12 Rare 33 (8-55)

Early tremor, late dementia

SCA13 Rare Childhood Unknown Mild mental retardation, short stature

DRPLA

Rare (USA) 20%

(Japan)

8 - 20 or 40 - 60's

Early onset correlates with

shorter duration Chorea, seizures, dementia, myoclonus

EA1 Unknown

1st decade (2-15)

Attenuates after 20 Myokymia; attacks last seconds to minutes; startle or

exercise induced; no vertigo

EA2 Unknown 3-52 Lifelong

Nystagmus; attacks last minutes to hours; posture change induced; vertigo; later permanent ataxia

Table 3. Examples of Autosomal Recessive Hereditary Ataxias: Molecular Genetics

Disease NameChromosome

LocusGen

eProtein

Test Availability

Friedreich ataxia (FRDA)

9q13-q21 FRDA1

Frataxin Clinical

Ataxia-telangiectasia (A-T)

11q22-q23 ATM PI3-kinase Clinical

Ataxia with vitamin E deficiency

(AVED) 8q13

TTPA

Alpha- tocopherol transfer protein

Clinical

IOSCA 10q23-q24 ? ? None

Marinesco- Sjögren ? ? ?

Spastic ataxia (ARSACS)

13q11 SAC

SSACSIN Research

Table 4. Examples of Autosomal Recessive Hereditary Ataxias: Clinical Features

Disease NamePopulation Frequency

Onset (Range in Years)

Duration (Years) Distinguishing Features

Friedreich ataxia (FRDA)

1-2/50,000 1st - 2nd decade (4-40)

10 - 30

Hyporeflexia, Babinski responses,

sensory loss, cardiomyopathy

Ataxia-telangiectasia

(A-T)

1/40,000 to 1/100,000

1st decade 10 - 20y Telangiectasia,

immune deficiency, cancer, chromosomal instability, increased alpha-fetoprotein

Ataxia with vitamin E

deficiency (AVED)

Rare 2-52 years,

usually <20 Decades

Similar to FRDA, head titubation (28%)

IOSCA Rare

(Finland) Infancy Decades

Peripheral neuropathy, athetosis, optic atrophy, deafness,

ophthalmoplegia

Marinesco- Sjögren

Rare Infancy Decades Mental retardation,

cataract, hypotonia, myopathy

Spastic ataxia (ARSACS)

Decades Childhood Spasticity,

peripheral neuropathy, retinal striation

IOSCA = Infantile onset spinocerebellar ataxia

PATHOGENESIS

Accumulation of glutamate @ cleft leads to degeneration of post synaptic neurons

Glutamate catabolism in brain glutamate in brain causing neuronal destruction from over excitation and degeneration

Plaitakis, et al. 1984

NMDA receptor mediated toxicity is most unifying hypothesis

Role of mutant proteins & inclusion bodies is not known

RECENT THEORIES

Botez’98

Drug cocktail L 5-HT(1000mg) , Amantidine (200mg) , Thiamine (50mg)

? Role - Remacemide ( NMDA recepter inhibiter in predominantly cerebellum )

? Role - Gabapentin ( Neuroprotective ) ? Role- Idebenone (Antioxidant )

Hypothesis of replacement and treatment in SCAs based on CSF 5-HIAA NMDA- receptor mediated toxicity CSF Thiamine Thiamine Rx 5-HIAA in pts with CSF -thiamine & 5-

HIAA Cerebral vulnerability with EC glutamate in

thiamine def. Pretreatment with NMDA recepter agonist MK-801

partially protects against thiamine induced brain lesions.

Pharmacotherapy

The Cerebellum 2004:3 107-111

Diagnostic Approach-Progressive imbalance

Subramony & Nance : Diagnosis and Management of the inherited ataxias. The Neurologist 1998; 4(6) :327-338

Autosomal recessive ataxias

Mariotti etal. J Neurology (2005) 252: 511 - 518

Autosomal Dominant

Mariotti etal. J Neurology (2005) 252: 511 - 518

Autosomal Dominant Ataxias

F:\ataxia\Spinocerebellar Ataxias.xls

A-TAX-IA

Cerebellar Dysfunction: Anatomy

Cerebellar lesion Signs

Posterior(Flocculo-nodular lobe Archicerebellum)

Eye movement disorders: Nystagmus; Vestibulo-ocular reflex (VOR)Postural and gait dysfunction

Midline(Vermis;Paleocerebellum)

Truncal & gait ataxia

Hemisphere(Neocerebellum)

Limb ataxia: Dysmetria, Dysdiadochokinesis, "intention" tremorDysarthriaHypotonia

Clinical Manifestations of Cerebellar Dysfunctions

• Cerebellum- modulates motor functions• Archicerebellum- ( flocculonodular node)

– Body equilibrium– Eye movements

• Paleocerebellum( vermis of ant. lobe pyramid , uvula and paraflocculus)– Input from spinal cord– Muscle tone – Axial stance and gait

• Neocerebellum (middle portion of vermis, cerebellar hemisphere)– Connected with pons and cortex through thalalmus – Planning and initiation of movements – Regulation of fine limb movements

03 01-06 approach to ataxia

Health & Medicine